The Fall of Tamoxifen?

Abstract:

Dramatic changes are taking place in the way post- menopausal patients with early-stage breast cancer are treated.Tamoxifen has been the cornerstone for treating hormone-responsive breast cancer of all stages in both pre- and post-menopausal women for over two decades.1 However, serious problems with tamoxifen including side effects, such as the fact it increases the risk of uterine cancer,1 and the fact that many patients develop tamoxifen resistance, led to identification of new hormonal therapies.

Aromatase inhibitors, which block the formation of estrogen in post-menopausal women, are not a new class of drug, but older aromatase inhibitors, such as aminogluthethimide were not selective in purely blocking the conversion of androgens to estrogens, and were somewhat abandoned as breast cancer therapies when tamoxifen was noted to have a superior toxicity profile.The newer aromatase inhibitors are all selective, and, in general, have an excellent safety profile.

Following encouraging data from trials2-6 examining the use of selective aromatase inhibitors in patients with advanced breast cancer, several trials were initiated to evaluate their use in post-menopausal patients with early- stage breast cancer. These trials can be broadly divided into those evaluating aromatase inhibitors head to head with tamoxifen, and trials in which aromatase inhibitors are used following some duration of tamoxifen.The first adjuvant aromatase inhibitor trial to report efficacy data was a head to head trial comparing the aromatase inhibitor, anastrozole, with tamoxifen. The Arimidex, Tamoxifen and Combination (ATAC) trial randomized over 9,000 post-menopausal patients with early-stage breast cancer using anastrozole, tamoxifen, or a combination of the two agents, for a total of five years.

The combination of tamoxifen and anastrozole did not result in a statistically significant better outcome than tamoxifen alone.7 However, significantly fewer patients with hormone receptor-positive breast cancer treated with anastrozole, compared with tamoxifen, have experienced disease relapse.7,8 At four years, disease-free survival is improved by almost 3% in patients treated with anastrozole, compared with patients treated with tamoxifen.8 Based on these results, anastrozole was approved in 2002 as adjuvant treatment for hormone receptor-positive breast cancer in post-menopausal patients. Five-year follow-up from the ATAC trial will be presented at the San Antonio Breast Cancer Symposium in December 2004.Survival data from the ATAC trial and data from several other trials that compare tamoxifen head-to-head with the other two aromatase inhibitors are eagerly awaited.

Over the past 12 months, several trials that examine the use of aromatase inhibitors after various durations of tamoxifen have reported preliminary efficacy data. The National Surgical Adjuvant Breast and Bowel Projects (NSABP) B-14 trial extension trial9 compared five years with 10 years of adjuvant tamoxifen in patients with node-negative early-stage breast cancer. Disease-free survival was statistically worse, and survival was not improved in patients who continued tamoxifen for 10 years, compared with patients who stopped tamoxifen at five years.9 It is clear that patients with estrogen receptor (ER)-positive breast tumors can experience recurrences many years after diagnosis, and the Oxford Overview Analysis1 has demonstrated that patients are at a high risk of recurrence after five years of tamoxifen.Therefore, it was essential to evaluate the use of newer hormonal agents in patients completing five years of tamoxifen.The MA-17 trial randomized about 4,500 patients to letrozole or placebo after they had completed five years of adjuvant tamoxifen. This trial was closed after the first interim analysis, due to a highly significant difference in estimated four-year disease-free survival in favor of the patients randomized to receive letrozole.10 The final analysis of this trial11 at 30 months follow-up demonstrates an absolute improvement in four-year disease-free survival of 7.5% and 2.7% in patients with node-positive and node- negative breast cancers,respectively,treated with letrozole, compared with those treated with placebo. Both distant disease-free and overall survival were significantly improved in patients treated with letrozole with node- positive tumors, but no statistical difference was seen in patients with node-negative tumors.11 In summary, the use of letrozole after tamoxifen improved outcome, particularly in patients with node-positive tumors. One issue with this trial is that the majority of patients randomized had not received the assigned five years of therapy when the trial was closed.Therefore,it is not clear what duration of letrozole is optimal after five years of tamoxifen. The NSABP B-33 trial, which randomized patients to exemestane or to placebo after five years of tamoxifen,was closed when the results of the MA-17 trial were made available. Based on the results of the MA-17 trial, letrozole was approved for extended adjuvant therapy in October 2004.

However, it remains unclear as to whether all patients require the complete five years of tamoxifen. Data from three trials now suggest that patients who switch to an aromatase inhbitor after two to three years of tamoxifen are less likely to experience disease recurrence than patients who receive five years of tamoxifen. An Italian group12 randomized approx- imately 400 patients who had completed about three years of adjuvant tamoxifen to either continue tamoxifen for the entire five years, or to switch to the aromatase inhibitor, aminogluthethimide. Patients who switched to the aromatase inhibitor were less likely to experience a visceral relapse, and had an improved overall survival and a trend to improved breast cancer survival, compared with patients receiving five years of tamoxifen.12